It is important that pharmaceutical products be effective and safe. Even when a pharmaceutical product is effective and safe immediately after production, if the drug is easily decomposed or denatured during storage and distribution of the pharmaceutical product, it is not considered to be effective and safe as a pharmaceutical product. Therefore, the stability of the drug is extremely important for pharmaceutical products.
To secure effectiveness and safety of a pharmaceutical product, not only the effectiveness and safety of the active ingredient itself are important but also the properties of the pharmaceutical preparation such as the drug dissolution property and the like in the body are extremely important. For example, when the dissolution of the drug from the pharmaceutical preparation is too late, the blood concentration of the drug does not reach an effective level, and the expected efficacy may not be sufficiently exhibited. On the other hand, when the dissolution of the drug from the preparation is too fast, the blood concentration of the drug increases sharply, causing a high risk of side effects.
In other words, pharmaceutical products are required to ensure, in addition to effectiveness and safety, the stability of the drug and a certain level of the drug dissolution property.
The dissolution property of a drug is known to correlate with the solubility thereof. In general, lower solubility of a drug is known to cause slower dissolution property of the drug.
A benzimidazole derivative having a strong angiotensin II receptor antagonistic activity, which is represented by the formula (I)
wherein R1 is a monocyclic nitrogen-containing heterocyclic group having a deprotonizable hydrogen atom, R2 is an esterified carboxyl group and R3 is an optionally substituted lower alkyl, or a salt thereof (hereinafter sometimes to be referred to as compound (I)), particularly (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate salt (patent document 1), is considered to be a promising therapeutic drug for hypertension and the like. However, the properties of a pharmaceutical preparation containing compound (I) need to be controlled to stabilize compound (I) because compound (I) is unstable in the neutral pH range, at which the pharmaceutical preparation is generally produced. Nevertheless, the solubility of compound (I) is low at the pH range where compound (I) is stable. In addition, a combination drug product composed of compound (I) and other active ingredient such as diuretic and the like cannot be easily formulated into a preparation superior in stability and dissolution property since the chemical properties are different.
As a combination drug product, a combination of a compound having an angiotensin II antagonistic activity and a compound having a diuretic action (patent document 2), and an internal solid preparation containing acetaminophen granules obtained by a separating granulation method to suppress the unpleasant taste and prevent discoloration of acetaminophen (patent document 3) are known. However, a combination drug product of compound (I) and a diuretic, which simultaneously affords drug stability and solubility, namely, dissolution property, has not been known.